Background and aims: CC chemokine receptor 2 (Ccr2) governs migration of inflammatory Ly6Chi monocytes from the bone marrow (BM) to the circulating blood, which is a key step for macrophage accumulation during progression of atherosclerosis. Hyperlipidemia is often accompanied by low AMP-activated kinase (AMPK) activity and increased expression of Ccr2. The aim of this study was to examine whether there is a link between AMPK and chemokine networks.
Methods: ApoE-/- mice were fed a western diet and treated daily with AMPK activators (AICAR, A769662, or Metformin) or vehicle for 10 weeks. The effect of AMPK activators on pro-inflammatory myeloid cell numbers within the BM, blood, spleen, and aorta of ApoE-/- mice was then examined.
Results: We found that AMPK activation significantly reduced the number of Ly6Chi monocytes in the blood and atherosclerotic plaques. This reduction was caused by down-regulation of Ccr2 protein expression, which inhibited Ccr2-mediated migration of Ly6Chi monocytes from the BM to the circulation. There was no effect on proliferation or apoptosis of BM-derived Ly6Chi monocytes. AMPK activation caused Ly6Chi monocytes to accumulate in the BM, with a concomitant reduction in numbers in the blood and spleen.
Conclusions: AMPK activation reduces the formation of atheromata-inducing macrophages in ApoE-/--deficient mice by inhibiting expression of Ccr2, thereby preventing the Ccr2-mediated migration of Ly6Chi monocytes from the BM. Therefore, AMPK may be a promising target for the treatment of atherosclerosis.
Keywords: AMPK; Atherosclerosis; Ccr2; Ly6C(hi); Migration; Monocyte.
Copyright © 2017. Published by Elsevier B.V.